Alkyl esters of alpha-acyl, alpha-acylamino, beta(3-indole)-propionic acid



Patented May 3, 1949 ALKYL ESTERS OF a-ACYL, a-ACYLAMINO, ,8 3 -IN DOLE)PROPIONIC ACID Noel F. Albertson, East Greenbush, and Sydney Archer andChester M. Suter, Albany, N. Y., assignors, by mesne assignments, toWinthrop- Stearns, Inc., New York, N. Y., a corporation of Delaware NoDrawing. Original application March 2, 1944,

Serial No. 524,776. Divided and this application August 1'7, 1948,Serial No. 44,806

1 Claim.

This invention relates to derivatives of indole, and to a novel methodof preparing them.

The invention has among its objects the preparation of indolederivatives substituted in the 3-position. Indole derivatives of thistype include especially indole-3-propionic acid, which is useful as aplant growth hormone, and B- indolyl-m-aminopropionic acid ortry-ptophane, which is one of the amino acids essential for humannutrition.

While indole-3-propionic acid and tryptophane have previously beensynthesized, for example, by methods involving the use ofindole-3-aldehyde or indole-3-glyoxylic acid, the synthetic methodsemployed leave much to be desired. One drawback is that the requisitestarting materials are rather difiicultly accessible, being obtainablefrom indole only in low yields. Other drawbacks to the prior proceduresinclude the necessity for preparing intermediates which are not readilypurified, the inclusion of steps requiring long reaction times, orreaction under pressure.

In contrast, the present invention affords a simple procedure forpreparing derivatives of indole-3-propionic acid by a new method notinvolving the drawbacks of prior procedures.

In essence, the new process comprises con- (lensing, under substantiallyanhydrous conditions and in the presence of a strong base, a Mannichbase of the indole series in which the(N-substituted-amino-l-methylgroup characteristic of Mannich bases isattached to the 3- carbon atom of the indole skeleton,

with an active hydrogen compound having the formula where X is hydrogenor acylamino, Y is carbalkoxyl or cyano, and Z is carbalkoxyl, cyano, oracyl, such as acetyl, propionyl, or benzcyl. The indole-3-propionic acidderivative thus obtained can be further decomposed or hydrolyzed, inaccordance with our invention, to form an indole V derivative having inthe 3-position the substituent where A is hydrogen or NHz, depending,respectively, on Whether X was hydrogen or acylamino.

The condensation reaction can conveniently be carried out by adding theMannich base to an alcoholic solution of the active hydrogen compound inthe presence of a metal alcoholate, and reaction is facilitated byadding to the mixture an accelerator which is an alkylating agent fortertiary amines.

If the condensation is carried out in alcohol, reaction may be hastenedby application of heat, for example, by refluxing the mixture forseveral hours, after which the reaction product can be isolated in anysuitable fashion. Thus, the alcohol may be removed by distillation invacuo and the residual oil or crystals partitioned between water and awater-immiscible organic solvent such as ether or chloroform. The waterlayer contains inorganic salts and quaternary ammonium salts. Thedesired condensation product is in the organic solvent, although,especially if ether is used, some of the condensation product may remainundissolved, if its solubility is limited. In either case, thecondensation product can readily be recovered. Y

While, above, it has been indicated that the condensation may beeffected most conveniently in a mutual solvent for the active hydrogencompound and. the Mannich base, such as a water-miscible alcohol, othersolvents customarily employed for effecting condensations withactivehydrogen compounds may be used. Such solvents include ethyl ether,benzene, butyl ether, and the like.

The condensation product is hydrolyzed and decomposed by treatment withdilute alkali, and then with dilute acid- If alkali is employed,acylamino groups like acetamido, benzamido, or phthalimido will notordinarily be hydrolyzed unless the conditions of hydrolysis are quitesevere. However, more readily hydrolyzed acylamino groups such ascarbethoxyamino are relatively easily hydrolyzed.

Alkali hydrolysis will convert the malonic ester 3 derivatives, and thecyanoacetic ester derivatives to metal salts of the correspondingmalonic acid derivative, and will convert acylacetic acid derivatives tothe corresponding propionic acid derivatives, all in accordance with thefollowing illustrative equations:

:The free-acids are of. course: readily obtained, for examplabyacidifying. aqueoussolutions of the metal salts.

-Acid hydrolysis V, will .hydrolyze acylamino groupszto. amino: and willalso decompose or delcarboxylate :a:-malonic-acid, with formation of the:propionicacid derivative. This is illustrated .by thefollowingequation:

methods for preparing Mannich bases, such-as the methods. shown. by:Blicke. Organic Reactions,

volume I, 303-341); can beiem'ployed.

It will be appreciated thatithezinvention'conntemplates: ;the.employment'rof. any vMannich base ot the indole. series,;:such :.a.'base beingsa .3- '(vB=.NI.CH2)1-indole which ..may. be further-substituted.;in-..the: indole a skeleton by groupings "not.v affectedunder-thev conditions. of formationof -a -Mannichbase, and suchsubstituents generally includinga-lkyl, alkoxyghalogen, nitro;acylamino,

and dialky'lamino. In the above expression for the basic substituent,(B=NCH2-), attached to the 3-carbon atom, the portion CH2- is derivedfrom the formaldehyde component, while the B=N-- portion is derived froman amine I-IN=B of the kind customarily employed in preparing Mannichbases. Here .alkyl B includes\ alkyl and divalent 'alkylene groups whichmay bear interrupting oxygen, sulfur, or nitrogen atoms.

Among such amines are dimethylamine, diethylamine, methylisobutylamine,morpholine, piperidine, methylbenzylamine, and the like. Other amineswhich-may-zbe employed for the preparation of the Mannichbases are givenby Blicke (loc. cit.)

The strong baseemployed to aid the condensation is conveniently analcoholate, such as sodium ethylate or potassium t-butylate, of astrongly electropositive metal, such as an alkali or alkaline earth ametal, ;;and including (sodium, ,ipotassium, magnesium, candy-calcium.13.11 66, .however, the base probably, reacts in-situwith the-active.hydrogen compound prior ,-to condensation, ,the ,:particularyanion of;the, strong base "is unimportant, providedonly that thebase iscapable-of, reacting, in a substantially anhydrous medium, :with ,the,ac tivehydrogen compound to form.- the .metal derivative of the latter.,-5I-Ienc e,-insteadotemploying a metal alcoholate, there mayibeusednther strong-v bases such ,as sodam-ide sodium triphenylmethide,sodium hydride, andithe like.

While the condensation -.wi1l ,proceed even in the presence ofconsiderably less than'an. equivalent ratio, of strongbase to active;hydrogen. 6. mpound, the, yields, under, these conditions ,are, lessthan if;-,a full.,-equivalent,.- or,apslight excess pf strong base ispresent, ,Hence in practicetit -is preferable to have suflicientbasepresent toreact with; all of the :active. hydrogen compound.

The active hydrogen, com qlmd employed in the condensation can ,be ethylmalonate, ethyl, acetoacetate, methyl acetoacetate, butyl 'acetoacetate,ethyl cyanoacetate, ethyl acetamidflmalonate,

.ethyl 1benzamidomalonate, .-;et yl pliithalimidomalonate,- ethyl1carbethoxyaminomalonate,.or the like.

As accelerators for the condensfation reaction there may be usedany;alkylating agent for ;t ertiary amines, such accelerators beingfurther characterized: by bein esters of ;,=,alcohols with stron acids.tz-Thez c eler t rslthus. contem late include y uiodide.emetb abremide,methyl chloride, methyl sulfate, ethyl iodide, butyl ptoluenesulfonate,benzyl chloride and in general other esters of strong acids such as thehydrohalic acids, sulfuric acid,;-sulfonic acids, etc. In practice, thechoice of accelerator is determined by considerations, of, economy,.ease ofwhandlingian ease of removal'from the reaction mixturepf anyunused accelerator and its decomposition products. The esters of thelower water-soluble alcohols best satisfy these requirements.

The accelerator apparently functions by alkylating the amino groupduring condensation, with formation of a quaternaryammonium groupingpermitting-more facile elimination of the amine moiety, perhaps 'in afashionanalogous to the -mechanism of the' Hofcrnann -degradation.Reaction'proceeds even in theabsence oi -the accelerator however; but it'is'--cons-iderab1yslower, and

hence in practice the use of an accelerator is to be preferred.

It will be appreciated that the invention also embraces new and valuableintermediates for the preparation of tryptophane. These intermediatesare compounds of the indole series having attached to the 3-carbon atomof the indole skeleton the sidechain Y! -oH,-o

where X is acylamino, Y is carboxyl, carbalkoxyl, or cyano, and Z iscarboxyl, carbalkoxyl, cyano, or acyl. For example, acylamino includesacetamido, benzamido, phthalimido, and carbethoxyamino. Carbalkoxylincludes --COOCH3, CC2H5, COO-isoCbH-z, -CO0nC4H9, and

so on.

The preferred compounds are those obtainable from the relatively readilyaccessible acylaminosubstituted malonic esters, -acetoacetic esters, and-cyanoacetic esters.

The following examples will serve further to illustrate the inventionwithout, however, limiting the scope of the invention thereto.

Example 1 One and fifteen-hundredths gram of sodium is dissolved in 100cc. of anhydrous ethyl alcohol and 10.9 grams of ethyl acetamidomalonateis added to the warm solution. To the resulting clear, colorlesssolution is added 8.7 g. of gramine (3- dimethylaminomethylindole).Seven and eighttenths grams of ethyl iodide in 20 cc. of anhydrous ethylalcohol is added over a period of forty-five minutes. An aliphatic amineodor is apparent as soon as the ethyl iodide is added. The mixture isrefluxed on a steam bath for six hours, during which time a gelatinousprecipitate of diethyldimethylammonium iodide is formed. Then thealcohol is removed from the reaction mixture under vacuum, and theresidue, a viscous oil, which sometimes crystallizes, is treated with 40cc. of water and 100 cc. of ethyl ether. After the mixture is warmed andshaken there is present a lower yellow aqueous layer, which containssodium salts and quaternary ammonium salts, and an upper pale yellowether layer which contains the major portion of the condensation productsuspended as a while crystalline solid. The solid is removed byfiltration. The ether solution is successively treated with dilutehydrochloric acid (to remove unreacted gramme), water, sodiumbicarbonate solution, and water and is then dried over sodium sulfate,filtered, and evaporated to dryness, whereby a small additional amountof product is obtained. A total of 11.2 g. of crude ethyl (3indolylmethyl) acetamidomalonate, which has the structural formula:

COOCQH;

6 the above procedure ethyl succinimido-cyaiioe acetate or ethylphthalimidoacetoacetate may be employed instead of ethylacetamidomalonate', and one thereby obtains an ester having the formulaOne and ninety-six hundredths gram of ethyl3-indolemethylacetamidomalonate is suspended in 100 cc. of watercontaining 10 g. of sodium hydroxide. The mixture is boiled for fifteenminutes, during the first half of which time all the solid dissolves.The solution is then cooled to about 10 C'. or lower and is maintainedat this temperature while concentrated hydrochloric acid is addeddropwise with cooling until the solution is acid to Congo red. A smallamount of white solid is precipitated. The solution is extracted fivetimes with 20 cc. portions of ethylether and the combined ether extractsare dried over sodium sulfate. The ether is removed under vacuum at atemperature below 30 C. There remains as a pale pink solid 1.56 g. of3-indolemethylacetamidomalonic acid. This substance exists in twopolymorphic forms, one ethersoluble and decomposing at about 108 0., theother ether-insoluble and decomposing at about 147 C.

Two and nine-tenths grams of either of the two polymorphic forms of3-indolemethylacetamidomalonic acid is suspended in 18 cc. of 2 Nsulfuric acid and the mixture is heated to boiling. There is a rapidevolution of carbon dioxide and after about fifteen minutes a. clearsolution is obtained. The solution is refluxed for two hours. To thedark red solution so obtained is added 10 cc. of 10% sodium hydroxidesolution and the gummy purple precipitate which forms is filtered off.The pH of the pale yellow filtrate is raised to about 5 by addition of10% sodium hydroxide solution. After a few minutes fine crystals oftryptophane will separate. The mixture is cooled and the solid iscollected on a filter. After drying at the yield of tryptophane is 1.03g. From the mother liquor, an additional 0.09 g. can be recovered. Theproduct decomposes at approximately 273 C.

Example 2 Twenty-three hundredths gram of sodium is dissolved in 10 cc.of anhydrous ethyl alcohol and to the solution is added 1.3 g. of ethylacetoacetate. To the resulting clear solution is added 3.30 g. ofgramine ethiodide. The mixture is refluxed on a steam bath for fourhours, after which the alcohol is removed under vacuum. The red-brownsyrupy residue is extracted with ethyl ether and the ether layer isretained. The ether is removed on a steam bath and the residue, which isethyl 3-indolemethylacetoacetate, is warmed on a steam bath for twohours with a aecaam 'sdlutionof .15 .g. .of..so.dium hydroxide in ,25-cc. of water. The solution .is diluted with several volumes of waterand filtered to remove any insoluble matter. The vfiltrate is acidifiedby addition of concentrated hydrochloric acid and .is then extractedwithethyl ether. The ether extract is dried over sodium sulfate. Afterremoval of the sodium sulfate :the 'ether is evaporated and the residueis dissolved in the minimum amount of ethyl alcohol. On additionalwater, the reaction product is precipitated asla white crystalline solidwhich is collected on a filter. The solid may be further purified byrecrystallization from water after treatment with charcoal. The product,which is ;3-;indolepropionic-acid, melts at approximately 132.

Instead of using ethyl acetoacetate in the above condensation, ethylcyanoacetate or ethyl malonate may be 'used. With gramine, these yield,respectively, .ethyl .a-cyano-fi-(3-indo1y1-)- propionate and. ethyl3-indolylmethylmalonate,

8 and both of these products, like ethyl .3-iindolylacetoacetate, can behydrolyzed to B-(;3-indole)- propionic acid.

This application is adivision of ourlconending U. .S. patent application.Ser. No. ,'524,!7!1fi, filed March 2, 19,44.

We claim:

An ester having the formula "'OHQ;CCOOR J o'=o x N OH;

where X is acylamino and :R is lower alkyl.

NOEL F. ,ALBERTSON. SYDNEY CHESTER SUTER.

No references cited.

